Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023)

AeRang Kim¹, Yao Lu², Scott H Okuno³, Denise Reinke⁴, Ophélia Maertens⁵, John Perentesis⁶, Mitali Basu⁶, Pamela L Wolters⁷, Thomas De Raedt⁵, Sant Chawla⁸, Rashmi Chugh⁹, Brian A Van Tine¹⁰, Geraldine O'Sullivan¹¹, Alice Chen¹¹, Karen Cichowski⁵, Brigitte C Widemann⁷

Affiliations

¹ Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010, USA.
² SARC Statistics, Weill Cornell Medicine Healthcare and Policy Research, 602 East 67 Street, New York, NY 10065, USA.
³ Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA.
⁴ SARC, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105, USA.
⁵ Children's Hospital of Philadelphia, Univeristy of Pennsylvania, 3501 Civic Center Boulevard, 19104 Philadelphia, PA, USA.
⁶ Cincinnati Children's Hospital & Uinviersity of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
⁷ Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
⁸ Sarcoma Oncology Center, 2811 Wilshire Blvd, Santa Monica, CA 90403, USA.
⁹ University of Michigan, 1500 E. Medical Center Dr., SPC 5912, Ann Arbor, MI 48109, USA.
¹⁰ Washington University in St. Louis, 660 S Euclid Ave., St. Louis, MO 63110, USA.
¹¹ National Cancer Institute, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, Bethesda, MD 20892, USA.

PMID: 32089640
PMCID: PMC7013290
DOI: 10.1155/2020/5784876

Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023)

AeRang Kim et al. Sarcoma. 2020.

. 2020 Jan 30:2020:5784876.

doi: 10.1155/2020/5784876. eCollection 2020.

Authors

Affiliations

¹ Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010, USA.
² SARC Statistics, Weill Cornell Medicine Healthcare and Policy Research, 602 East 67 Street, New York, NY 10065, USA.
³ Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA.
⁴ SARC, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105, USA.
⁵ Children's Hospital of Philadelphia, Univeristy of Pennsylvania, 3501 Civic Center Boulevard, 19104 Philadelphia, PA, USA.
⁶ Cincinnati Children's Hospital & Uinviersity of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
⁷ Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
⁸ Sarcoma Oncology Center, 2811 Wilshire Blvd, Santa Monica, CA 90403, USA.
⁹ University of Michigan, 1500 E. Medical Center Dr., SPC 5912, Ann Arbor, MI 48109, USA.
¹⁰ Washington University in St. Louis, 660 S Euclid Ave., St. Louis, MO 63110, USA.
¹¹ National Cancer Institute, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, Bethesda, MD 20892, USA.

PMID: 32089640
PMCID: PMC7013290
DOI: 10.1155/2020/5784876

Abstract

Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. Patients and Methods. In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain.

Results: Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m² intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1-4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable.

Conclusion: Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).

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Conflict of interest statement

D. Reinke reports grant from Department of Defense and other support from Synta Pharmaceuticals. P. Wolters reports holdings from Bristol-Meyers Squibb, Inc., and a grant from the Neurofibromatosis Therapeutic Acceleration Program outside the submitted work. S. Chawla reports other support from Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC, and Janssen outside the submitted work. R. Chugh reports grants from AADi, Novartis, Lilly, Medivation, Plexiconn, Pfizer, Advenchen, Morphotek, and Mabvax; grants and personal fees from Epizyme; and personal fees from Janssen and Immune Design outside the submitted work. Brian Van Tine reports grants from Pfizer and Merck and other support from Janssen, Epizyme Daiichi Sankyo, Blueprint Medicine, Immune Design, Janssen, Caris, and Lilly outside this work. No potential conflicts of interest were disclosed by the other authors.

Figures

**Figure 1**
Aggregate pharmacodynamic responses to ganetespib and sirolimus therapy.

See this image and copyright information in PMC

References

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Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023)

Affiliations

Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023)

Authors

Affiliations

Abstract

Conflict of interest statement

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